Research Article - Neuropsychiatry (2016) Volume 6, Issue 2
MTHFR Gene Polymorphism Positive Treatment-Resistant Depression: Prevalence and Treatment Recommendations
- Corresponding Author:
- Robert P Duprey
Jr., Oceania University of Medicine, MSII& MSN, MA, APRN-RX, PMHNP-BC, 1151 Aquidneck Ave, #417, Middletown, RI 02842, USA
Major depressive disorder (MDD) is a treatable mood disorder with an estimated 15.7 million adults aged 18 or older in the United States having at least one major depressive episode in the past year . This number represents a prevalence of 6.7% of all adults in the US population. Ten to 15% of MDD cases can be classified as treatment resistant (TR).
Treatment resistant; Depression; MTHFR; Folic acid
Major depressive disorder (MDD) is a treatable mood disorder with an estimated 15.7 million adults aged 18 or older in the United States having at least one major depressive episode in the past year . This number represents a prevalence of 6.7% of all adults in the US population [1,2]. Ten to 15% of MDD cases can be classified as treatment resistant (TR) [3,4]. The prevailing theory of MDD is rooted in neurobiology and the monoamine neurotransmitters serotonin (5HT), norepinephrine (NE), and dopamine (DA), in a series of neural circuits in the brain that contribute to depressive symptoms [3,5-7]. Within this medical biological model, methylenetetrahydrofolate reductase (MTHFR) genetic mutations cause low levels of MTHFR enzyme. Low enzyme levels cause low methylenetetrahydrofolate (MTHF) levels. Low levels of MTHF cause lower levels of monoamines. Lastly, lower levels of monoamine neurotransmitters causes MDD. Thus, MDD is in part associated with a folate metabolism deficiency.
TR patients have little-to-no response to psychopharmacotherapy, which may include trials of different anti-depressant medications, a combination of psychotropic agents, adjunctive therapy, or off-label use of alternative agents [3,4]. TR MDD is known to be associated with the MTHFR gene polymorphism [3-5]. While this association is well-known in TR MDD, little has been published specifically regarding the prevalence of the mutation specific to TR MDD nor the frequency of the polymorphism in the homozygous (677TT) or heterozygous (677CT) state.
The goals of this study are to (a) determine the prevalence of the MTHFR mutation specific to TR MDD, (b) ascertain the prevalence of the 677CT and 677TT MTHFR gene polymorphisms, and (c) make treatment recommendations. Based on our reviewed literature and preliminary data, we suspect (a) the overall prevalence of the MTHFR mutation to be higher in TR MDD than in non-TR MDD and the general population and (b) the heterozygous presentation are more prevalent. To date, no study has directly addressed the prevalence of MTHFR mutation in TR MDD with the emphasis on treatment resistance, or the prevalence of the polymorphic 677CT or 677TT gene states.
A cross-sectional retrospective study was conducted between January 2015 and May 2016. Institutional Review Board and Ethics Committee approval was granted through Newport County Community Mental Health Center and Oceania University of Medicine. Because this was a retrospective study, no recruitment was required. A convenience sample of the author’s clinical patients already enrolled in care from a community mental health center in coastal Rhode Island was used. Patients were already receiving the standard of care for TR MDD to include genetic testing for the MTHFR gene. Age, race, and ethnicity were not accounted for in the sample. A total of 29 TR cases were identified. Inclusion criteria required: (a) the diagnosis of MDD based on DSM V diagnostic criteria , (b) evidence of treatment resistance [3,4] and (c) having already been genetically tested for the MTHFR polymorphism. Laboratories used for testing included patient-selected laboratories as part of their routine medical care. Genetic testing was conducted in accordance with these laboratory standards.
Of the 29 treatment resistant cases genetically tested, 22 cases (76%) were positive for the MTHFR mutation. Of these 22 recorded TR MDD patients positive for the MTHFR polymorphism, 17 (77%) were heterozygous, and 5 (23%) were homozygous, giving a ratio of 3.4:1 for the heterozygous to homozygous state.
Studies [8-12] have addressed the risk of developing mental illnesses, given a particular allele frequency of the MTHFR gene, and its association as a factor, or contributing cause, of TR depression. Although these studies did not directly address specific allele prevalence, data were extracted for the purpose of comparing the prevalence of the polymorphic gene frequencies to the current study. El-Hadidy  resulted 52 cases (80%) of 677CT and 13 cases (20%) of 677TT. Peer booms  resulted 1487 677CT cases (80%) and 363 677TT cases (20%). Gilbody  resulted 563 677CT cases (78%) and 161 677TT cases (22%). Flint  meta-analysis data found 20% of MDD cases (not identified as TR) positive for the MTHFR gene. The prevalence of these mutations in the general population who do not suffer from MDD is reported in Gilbody to be between 2-20% with variance depending on ethnicity and geographic location. Gilbody metaanalysis data compared depression rates for individuals with given allele presentations and found MDD occurred in 11% of individuals positive for either MTHFR T allele presentation (compared to 7% prevalence of MDD in the general population) . Age, race, and ethnicity were not extracted from the above studies.
The mutation of the MTHFR gene is a single nucleotide polymorphism that causes an alanine-to-valine amino acid substitution [8,13-15]. For the 677T polymorphism, homozygote variants have 30% enzyme activity in comparison with homozygotes for the wild-type 677C allele, while heterozygotes retain 65% wild-type MTHFR enzyme activity [8,16]. The wild type MTHFR gene is 677CC .
The major assumption in this study is that the MTHFR polymorphism is important in TR MDD cases. Other symptoms and risks of MDD may respond to or be mitigated by psychopharmacology with psychotherapy. One limitation is the small sample size. The 29 TR MDD patients identified in this study represents about 8% of the author’s total patient case load (#345). The 29 TR MDD cases from the current study furthermore represent 11% the case load from patients with a depressive disorder diagnosis (#275) consistent with above reported 10 to 15% [3,4] of all MDD patients are TR. The current study’s 22 TR MDD cases positive for the MTHFR polymorphism represents 11% out of all MDD cases in the author’s caseload. This is less than the reported 20%  of cases out of all MDD cases positive for MTHFR mutation. When compared to the general population without MDD, the percentage of people positive for the MTHFR polymorphism is 2 to 20% , similar to the 20%  reported for all MDD patients positive for the MTHFR polymorphism. One could say there is little difference between MDD and the general population in individuals positive for the MTHFR polymorphism. Of the author’s total caseload, the 22 MTHFR positive cases represent 8% of the total caseload, consistent with that reported in general population (2-20%) and less than that out of all MDD cases reported above, (20%). While reported data showed that 20%  of all MDD cases are positive for the MTHFR polymorphism, the current study accounted for the dimension of treatment resistance and found 76% of TR MDD positive for the polymorphism.
From our data, MDD cases identified as TR have a 74% chance of being positive for the MTHFR genetic polymorphism. Clinically this is relevant in that current recommended therapies for MTHFR polymorphism are high doses of folic acid (2-7 mg) or L-methylfolate (7.5-15 mg) [18,19]. This stands to yield better outcomes in the treatment of TR MDD than standard therapies alone which by the nature of being TR have already failed trials of psychotropic agents. Genetic testing for the MTHFR polymorphism is recommended where feasible, however the results of the current study would indicate that once identified as TR, MDD patients are likely to be MTHFR polymorphism positive and therefore genetic testing is not required for recommended treatment to begin. The results of the current study are also consistent with extracted data from the literature review that the heterozygous polymorphism occurs at a ratio of approximately 3.4:1 when compared to the homozygous polymorphism state. Thus, the heterozygous presentation is more prevalent in TR MDD cases positive for the MTHFR polymorphism. That is, a 77% chance of the MTHFR gene being 65% functional. Given that the results of the current study are consistent with extracted data from the existing literature, generalizability can be extended to all patients with TR MDD.
In conclusion, once identified as TR MDD with a 76% likelihood of being positive for the MTHFR polymorphism and a 77% chance of this being heterozygous (with 65% functionality) [8,16], we recommend the use of treatments at the lower dose range (folic acid 4 mg and L-Methylfolate at 7.5 mg) [18,19].
We are grateful for the support and encouragement from colleagues, staff, and physicians at Newport County Community Mental Health Center (NCCMHC) Middletown, RI. A special expression of gratitude is extended to Francis L.” Butch" Paranzino, MSW, LICSW Vice President and Chief Operating Officer and Mary Jane Creely, MS, RN, PMHCNS-BC Vice President, Nursing, Quality Improvement & Human Resources both from NCCMHC. Special gratitude is further expressed for the encouragement and guidance provided by Oceania University of Medicine faculty and staff and expressed especially to Dr.’s Cunningham, Dolberry, and Brown for support, guidance, editing, and contributions. Scott Cunningham, MD is Oceania University of Medicine’s Chief Academic Officer/Curriculum Consultant. Randall Brown PhD is Oceania University of Medicine’s North American Deputy Vice Chancellor and Professor. Dr. Adrienne Dolberry PhD is an OUM Academic & Research Advisor and Instructor.
The views expressed herein are those of the authors and do not necessarily reflect the views of the Department of Defenses or NCCMHC.
There were no biomedical financial interests or potential conflicts of interest. This study was conducted with no costs to patients, healthcare organizations, or care costs outside of normal treatment protocols.
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